The goal of this proposal is to develop a novel approach how to ablate tumor cells, while leaving healthy cells alive. This approach is based on 123I, a radioactive iodine isotope that emits Auger electrons. Auger electrons have the advantage of dissipating their energy in a very narrow radius, principally confined to only 10 nanometers. They therefore inflict cellular damage only at their targeted site, which is in stark contrast to other forms of radioactive emission. We intend to target the DNA of cancer cells by conjugating 123I to inhibitors of the DNA repair enzyme PARP1. These inhibitors have shown to accumulate in the nuclei of cancer cells, and we have demonstrated that they are particularly useful for the delivery of targeted payloads to brain tumors. Auger emitting PARP1 targeted radiopharmaceuticals are less likely to damage kidney and liver than ?- or ?- emitting radionuclides, because in those organs, the overwhelming amount of activity should be retained outside of the nucleus, where the toxicity of Auger emitters is significantly lower. The ultimate goal of this study is to validate PARP1 targeted shuttles for Auger emitters in mouse models of glioblastoma. We envision that Auger emitters can be used to ablate tumor tissues, while at the same time toxicity to excretory organs can be kept to a minimum. All experiments will be performed at the Department of Radiology of Memorial Sloan-Kettering Cancer. For this application, an interdisciplinary team of experts has been brought together to aid in the translation of this technology. The research team will include Dr. Thomas Reiner (Radiochemistry and Imaging Sciences), Dr. Wolfgang Weber (Nuclear Medicine), Dr. Mitat G?nen (Biostatistics) and Dr. John Humm (Medical Physics). Together, they form an ideal team to pursue this novel research avenue, bringing together expertise from a wide variety of disciplines. The specific aims of this proposal are to first synthesize a small library of 123I-labeled PARP1 targeted inhibitors and evaluate them as potential radiotherapeutic drugs. We will select the most successful candidates based on their binding characteristics, solubility and serum stability. Pharmacokinetic and -dynamic data will be obtained for all compounds, and the radiation dose to the tumors and normal organs determined. The lead PARP1 inhibitor (123I-iPARP1) with the most suitable pharmacokinetic profile (based on tumor uptake, in vitro efficacy, off-target accumulation, blood and tissue clearance) will be identified. It will be used o assess the therapeutic potential of radioiodine-labeled PARP1 inhibitors in mouse models of glioblastoma. We will perform a dose escalation study in xenograft as well as orthotopic models, administering 123I-iPARP1, both systemically as well as locally, and measure the effects on tumor growth and systemic toxicity. If successful, the generated data will form the foundation for a R01 application involving the same research team. We envision to study the lead 123I-iPARP1 construct in infiltrative mouse models of glioblastoma, and ultimately performing clinical trials at MSKCC.